US5587497A - 19-nor-vitamin D compounds - Google Patents
19-nor-vitamin D compounds Download PDFInfo
- Publication number
- US5587497A US5587497A US08/442,492 US44249295A US5587497A US 5587497 A US5587497 A US 5587497A US 44249295 A US44249295 A US 44249295A US 5587497 A US5587497 A US 5587497A
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- Prior art keywords
- vitamin
- hydroxy
- hydrogen
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to biologically active vitamin D compounds. More specifically, the invention relates to 19-nor-analogs of 1.sub. ⁇ -hydroxylated vitamin D compounds and to a general process for their preparation.
- Important examples of such analogs are 1 ⁇ -hydroxyvitamin D 3 , 1 ⁇ -hydroxyvi tamin D 2 , various side chain fluorinated derivatives of 1 ⁇ ,25-dihydroxyvitamin D 3 , and side chain homologated analogs.
- a class of 1 ⁇ -hydroxylated vitamin D compounds not known heretofore are the 19-nor-analogs, i.e. compounds in which the ring A exocyclic methylene group (carbon 19) typical of all vitamin D system has been removed and replaced by two hydrogen atoms. Structurally these novel analogs are characterized by the general formula I shown below: ##STR2## where X 1 and X 2 are each selected from the group consisting of hydrogen and acyl, and where the group R represents any of the typical side chains known for vitamin D type compounds.
- R may be an alkyl, hydrogen, hydroxyalkyl or fluoroalkyl group, or R may represent the following side chain: ##STR3## wherein R 1 represents hydrogen, hydroxy or O-acyl, R 2 and R 3 are each selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group --(CH 2 ) m --where m is an integer having a value of from 2 to 5, R 4 is selected from the group consisting of hydrogen, hydroxy, fluorine, O-acyl, alkyl, hydroxyalkyl and fluoroalkyl, R 5 is selected from the group consisting of hydrogen, fluorine, alkyl hydroxyalkyl and fluoroalkyl, or, R 4 and R 5 taken together represent double-bonded oxygen, R 6 and R 7 are each selected from the group consisting of hydrogen, hydroxy, O-acyl, fluorine and alkyl, or, R 6 and R 7 taken together form a carbon-carbon double bond
- side chains are the structures represented by formulas (a), (b), (c), (d) and (e) below, i.e. the side chain as it occurs in 25-hydroxyvitamin D 3 (a); vitamin D 3 (b); 25-hydroxyvitamin D 2 (c) ; vitamin D 2 (d) ; and the C-24-epimer of 25-hydroxyvitamin D 2 (e). ##STR4##
- alkyl ⁇ signifies an alkyl radical of 1 to 5 carbons in all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, etc.
- ⁇ hydroxyalkyl ⁇ and ⁇ fluoroalkyl ⁇ refer to such an alkyl radical substituted by one or more hydroxy or fluoro groups respectively
- ⁇ acyl ⁇ means an aliphatic acyl group of 1 to 5 carbons, such as formyl, acetyl, propionyl, etc. or an aromatic acyl group such as benzoyl, nitrobenzoyl or halobenzoyl.
- ⁇ aryl ⁇ signifies a phenyl-, or an alkyl-, nitro- or halo-substituted phenyl group.
- the preparation of 1.sub. ⁇ -hydroxy-19-nor-vitamin D compounds having the basic structure shown above can be accomplished by a common general method, using known vitamin D compounds as starting materials.
- Suitable starting materials are, for example, the vitamin D compounds of the general structure II: ##STR5## where R is any of the side chains as defined above.
- These vitamin D starting materials are known compounds, or compounds that can be prepared by known methods.
- the hydroxy group is converted to the corresponding acyl derivative, i.e. the compound III shown above, where X represents an acyl group, using standard acylation procedures, such as treatment with an acyl anhydride or acyl halide- in pyridine at room temperature or slightly elevated temperature (30°-70° C.).
- acyl protection of hydroxy functions alternative standard hydroxy-protecting groups can also be used, such as, for example, alkylsilyl or alkoxyalkyl groups.
- Such protecting groups are well-known in the art. (e.g.
- the acylation of the 1 ⁇ -hydroxy group as mentioned above will simultaneously effect the acylation of side chain hydroxy functions, and these acylation conditions can, of course, be appropriately adjusted (e.g. elevated temperatures, longer reaction times) so as to assure complete protection of side chain vicinal diol groupings.
- the next step of the process comprises the reduction of the 10-oxo-group to the corresponding 10-alcohol having the structure VI shown below (where X is acyl and Y represents hydroxy).
- X is acyl
- this reduction is carried out conveniently in an organic solvent at from about 0° C. to about room temperature, using NaBH 4 or equivalent hydride reducing agents, selective for the reduction of carbonyl groups without cleaving ester functions.
- any of the other hydride reducing agents e.g. LiAlH 4 , or analogous reagents
- any of the other hydride reducing agents e.g. LiAlH 4 , or analogous reagents
- the 10-hydroxy intermediate is then treated with an alkyl- or arylsulfonylhalide (e.g. mathanesulfonylchloride) in a suitable solvent (e.g. pyridine) to obtain the corresponding 10-O-alkyl--or arylsulfonyl derivative (the compound having the structure shown VI above where Y is alkyl-SO 2 O-, or aryl-SO 2 O-, and this sulfonate intermediate is then directly reduced, with lithiun aluminum hydride, or the analogous known lithium aluminum alkyl hydride reagents in an ether solvent, at a temperature ranging from 0° C.
- an alkyl- or arylsulfonylhalide e.g. mathanesulfonylchloride
- a suitable solvent e.g. pyridine
- the hydroxy groups at C-1 can be reprotected by acylation or silylation or ether formation to the corresponding acyl, alkylsilyl or alkoxyalkyl derivative, but such protection is not required.
- Alternative hydroxy-protecting groups, such as alkylsilyl or alkoxyalkyl groups would be retained in this reduction step, but can be removed, as desired, at this or later stages in the process by standard methods known in the art.
- the separated monoacetates of structure VII or VIII or the free 1,3-dihydroxy compound can, of course, be reacylated according to standard procedures with any desired acyl group, so as to produce the product of structure I above where X 1 and X 2 represent acyl groups which may be the same or different.
- novel compounds of this invention exhibit an unexpected parttern of biological activity, namely high potency in promoting the differentiation of malignant cells and little or no activity in calcifying bone tissue. This is illustrated by the biological assay results obtained for 1 ⁇ ,25-dihydroxy-19-nor-vitamin D 3 (compounds Ia), which are summarized in Tables 1 and 2, respectively.
- Table 1 shows a comparison of the activity of the known active metabolite 1 ⁇ ,25-dihydroxyvitamin D 3 and the 19-nor analog (Ia) in inducing the differentiation of human leukemia cells (HL-60 cells) in culture to normal cells (monocytes).
- Differentiation activity was assessed by three standard differentiation assays, abbreviated in Table 1 as NBT (nitroblue tetrazolium reduction), NSE (non-specific esterase activity), and PHAGO (phagocytosis activity).
- the assays were conducted according to known procedures, as given, for example, by DeLuca et el. (U.S. Pat. No. 4,717,721) and Ostrem et el., J. Biol. Chem. 262, 1416, 1987).
- the differentiation activity of the test compounds is expressed in terms of the percent of HL-60 cells having differentiated to normal cells in response to a given concentration of test compound.
- the new 19-nor analog (Ia) exhibits no activity in an assay measuring the calcification of bone, a typical response elicited by vitamin D compounds.
- Relevant data, representing the results of an assay comparing the bone calcification activity in rats of 1 ⁇ ,25-dihydroxyvitamin D 3 and 1 ⁇ ,25-dihydroxy-19-nor-vitami D 3 (Ia) are summarized in Table 2. This assay was conducted according to the procedure described by Tanaka et al., Endocrinology 92, 417 (1973).
- the new 19-nor analog shows a selective activity profile combining high potency in inducing the differentiation of malignant cells with very low or no bone calcification activity.
- the compounds of this novel structural class therefore, can be useful as therapeutic agents for the treatment of malignancies Because the differentiative activity of vitamin D compounds on keratinocytes of skin (Smith et el., J. Invest. Dermatol. 86, 709, 1986; Smith et el., J. Am. Aced. Dermatol. 19, 516, 1988) is believed to be an indication of successful treatment of psoriasis (Takamoto et al., Calc. Tissue Int.
- these compounds should prove useful in treating this and other skin disorders characterized by proliferation of undifferentiated skin cells. These compounds should also find use in the suppression of parathyroid tissue, as for example, in cases of secondary hyperparathyroidism found in renal disease (Slatopolsky et al., J. Clin. Invest. 74, 2136, 1984).
- the novel compounds of this invention can be formulated as solutions in innocuous solvents, or as emulsions, suspensions or dispersions in suitable innocuous solvents or carriers, or as pills, tablets or capsules, containing solid carriers according to conventional methods known in the art.
- the compounds are advantageously formulated as creams or ointments or similar vehicle suitable for topical applications. Any such formulations may also contain other pharmaceutically-acceptable and non-toxic excipients such as stabilizers, anti-oxidants, binders, coloring agents or emulsifying or taste-modifying agents.
- the compounds are advantageously administered by injection, or by intravenous infusion of suitable sterile solutions, or in the form of oral doses via the alimentary canal, or topically in the form of ointments, lotions, or in suitable transdermal patches.
- suitable sterile solutions or in the form of oral doses via the alimentary canal, or topically in the form of ointments, lotions, or in suitable transdermal patches.
- the 19-nor-vitamin D compounds of this invention are administered to subjects in dosages sufficient to inhibit the proliferation of malignant cells and induce their differentiation into normal monocyte-macrophages.
- the compounds may be administered orally or topically in amounts sufficient to arrest the proliferation of undifferentiated keratinocytes, and in the treatment of hyperparathyroidism, the compounds are administered in dosages sufficient to suppress parsthyroid activity, so as to achieve parathyroid hormone levels in the normal range.
- Suitable dosage amounts are from 1 to 500 ⁇ g of compound per day, such dosages being adjusted, depending on diseases to be treated, its severity and the response or condition of the subject as well-understood in the art.
- this diol cleavage reaction does not require elevated temperatures, and it is, indeed, generally prefereable to conduct the reaction at approximately room temperature.
- Both 19-nor-1,25-dihydroxyvitamin D 3 acetates VIIa and VIIIa were hydrolyzed in the same manner.
- Each of the monoacetates was dissolved in 0.5 ml of ether and 0.5 ml 0.1 N KOH in methanol was added. The mixture was stirred under argon atmosphere for 2 h. More ether was added and the organic phase washed with brine, dried over anhydrous MgSO 4 , filtered and evaporated. The residue was dissolved in a 1:1 mixture of 2-propanol and hexane and passed through a Sep Pak column and washed with the same solvent.
Abstract
Description
TABLE 1 ______________________________________ Differentiation of HL-60 Cells % Differentiated Cells (mean ± SEM) NBT NSE PRAGO ______________________________________ 1α,25-dihydroxyvitamin D.sub.3 (moles/liter) 1 × 10.sup.-7 86 ± 2 89 ± 1 87 ± 3 1 × 10.sup.-8 60 ± 2 60 ± 3 64 ± 2 1 × 10.sup.-9 33 ± 2 31 ± 2 34 ± 1 1α,25-Dihydroxy-19-nor- vitamin D.sub.3, (Ia) (moles/liter) 2 × 10.sup.-7 94 ± 2 95 ± 3 94 ± 2 1 × 10.sup.-7 90 ± 4 84 ± 4 90 ± 4 5 × 10.sup.-8 72 ± 3 73 ± 3 74 ± 3 1 × 10.sup.-8 61 ± 3 60 ± 3 56 ± 1 1 × 10.sup.-9 32 ± 1 31 ± 1 33 ± 1 ______________________________________
TABLE 2 ______________________________________ Calcification Activity Total Amount % Ash Ash (mg) Administered* (mean ± (mean ± Compound (pmoles/day/7 days) SEM) SEM) ______________________________________ D (control) 0 19 ± 0.8 23 ± 1.2 1α,25-dihydroxy- 32.5 23 ± 0.5 34 ± 1.6 vitamin D.sub.3 65.0 26 ± 0.7 36 ± 1.1 325.0 28 ± 0.9 40 ± 1.9 1α,25-dihydroxy-19- 32.5 22 ± 0.9 28 ± 1.6 nor-vitamin D.sub.3 (Ia) 65.0 19 ± 1.5 28 ± 3.4 325.0 19 ± 1.2 30 ± 2.4 ______________________________________ *Each assay group comprised 6 rats, receiving the indicated amount of tes compound by intraperitoneal injection daily for a period of seven days.
Claims (12)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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US08/442,492 US5587497A (en) | 1989-03-09 | 1995-05-16 | 19-nor-vitamin D compounds |
US08/626,431 US5880113A (en) | 1989-03-09 | 1996-04-25 | 19-nor-vitamin D compounds |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US32103089A | 1989-03-09 | 1989-03-09 | |
US07/481,354 US5237110A (en) | 1989-03-09 | 1990-02-16 | 19-nor-vitamin d compounds |
US55740090A | 1990-07-23 | 1990-07-23 | |
US87970692A | 1992-05-05 | 1992-05-05 | |
US07/960,241 US5246925A (en) | 1989-03-09 | 1992-10-13 | 19-nor-vitamin D compounds for use in treating hyperparathyroidism |
US08/123,485 US5342975A (en) | 1989-03-09 | 1993-09-17 | 19-nor-vitamin D compounds |
US28126194A | 1994-07-27 | 1994-07-27 | |
US08/442,492 US5587497A (en) | 1989-03-09 | 1995-05-16 | 19-nor-vitamin D compounds |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US28126194A Division | 1989-03-09 | 1994-07-27 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US08/626,431 Division US5880113A (en) | 1989-03-09 | 1996-04-25 | 19-nor-vitamin D compounds |
Publications (1)
Publication Number | Publication Date |
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US5587497A true US5587497A (en) | 1996-12-24 |
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Family Applications (7)
Application Number | Title | Priority Date | Filing Date |
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US07/481,354 Expired - Lifetime US5237110A (en) | 1989-03-09 | 1990-02-16 | 19-nor-vitamin d compounds |
US08/442,488 Expired - Lifetime US5633241A (en) | 1989-03-09 | 1995-05-16 | 19-nor-vitamin D compounds |
US08/442,462 Expired - Lifetime US5561123A (en) | 1989-03-09 | 1995-05-16 | Method of treating proliferative skin disorders with 19-nor-vitamin D compounds |
US08/442,492 Expired - Lifetime US5587497A (en) | 1989-03-09 | 1995-05-16 | 19-nor-vitamin D compounds |
US08/442,483 Expired - Lifetime US5618805A (en) | 1989-03-09 | 1995-05-16 | 19-nor-vitamin D compounds |
US08/558,221 Expired - Fee Related US5710294A (en) | 1989-03-09 | 1995-11-17 | 19-nor vitamin D compounds |
US08/626,431 Expired - Fee Related US5880113A (en) | 1989-03-09 | 1996-04-25 | 19-nor-vitamin D compounds |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
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US07/481,354 Expired - Lifetime US5237110A (en) | 1989-03-09 | 1990-02-16 | 19-nor-vitamin d compounds |
US08/442,488 Expired - Lifetime US5633241A (en) | 1989-03-09 | 1995-05-16 | 19-nor-vitamin D compounds |
US08/442,462 Expired - Lifetime US5561123A (en) | 1989-03-09 | 1995-05-16 | Method of treating proliferative skin disorders with 19-nor-vitamin D compounds |
Family Applications After (3)
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US08/442,483 Expired - Lifetime US5618805A (en) | 1989-03-09 | 1995-05-16 | 19-nor-vitamin D compounds |
US08/558,221 Expired - Fee Related US5710294A (en) | 1989-03-09 | 1995-11-17 | 19-nor vitamin D compounds |
US08/626,431 Expired - Fee Related US5880113A (en) | 1989-03-09 | 1996-04-25 | 19-nor-vitamin D compounds |
Country Status (15)
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US (7) | US5237110A (en) |
JP (1) | JPH0667899B2 (en) |
KR (1) | KR950013636B1 (en) |
AR (1) | AR246254A1 (en) |
AU (1) | AU632315B2 (en) |
BR (1) | BR9004521A (en) |
CA (1) | CA1333616C (en) |
FI (1) | FI905489A0 (en) |
HU (2) | HU215604B (en) |
IL (1) | IL93455A (en) |
NO (1) | NO904854D0 (en) |
RO (1) | RO109331B1 (en) |
RU (2) | RU2055068C1 (en) |
WO (1) | WO1990010620A1 (en) |
ZA (1) | ZA907119B (en) |
Cited By (44)
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US5843928A (en) * | 1997-03-17 | 1998-12-01 | Wisconsin Alumni Research Foundation | 2-alkylidene-19-nor-vitamin D compounds |
US5880113A (en) * | 1989-03-09 | 1999-03-09 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D compounds |
US5939406A (en) * | 1997-07-21 | 1999-08-17 | Wisconsin Alumni Research Foundation | 18-substituted-19-nor-vitamin D compounds |
US5945410A (en) * | 1997-03-17 | 1999-08-31 | Wisconsin Alumni Research Foundation | 2-alkyl-19-nor-vitamin D compounds |
US5962707A (en) * | 1998-08-18 | 1999-10-05 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D3 compounds with calcemic activity |
US6017907A (en) * | 1993-07-09 | 2000-01-25 | Laboratoire Theramex S.A. | Structural analogues of vitamin D |
US6306844B1 (en) | 1997-03-17 | 2001-10-23 | Wisconsin Alumni Research Foundation | Use of 2α-methyl-19-nor-20(S)-1α, 25-dihydroxyvitamin D3 to increase bone strength |
US6316642B1 (en) | 1997-03-17 | 2001-11-13 | Wisconsin Alumni Research Foundation | 26,27-Homologated-20-EPI-2alkyl-19-nor-vitamin D compounds |
US6359152B2 (en) | 1997-07-21 | 2002-03-19 | Wisconsin Alumni Research Foundation | 18-substituted-19-nor-vitamin D compounds |
US6392071B1 (en) * | 1997-03-17 | 2002-05-21 | Wisconsin Alumni: Research Foundation | 26,27-homologated-20-EPI-2-alkylidene-19-nor-vitamin D compounds |
US6440953B1 (en) | 2000-09-08 | 2002-08-27 | Wisconsin Alumni Research Foundation | 1α-hydroxy-2-methylene-19-nor-homopregnacalciferol and its uses |
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US6627622B2 (en) | 2002-02-18 | 2003-09-30 | Wisconsin Alumni Research Foundation | (20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol and its uses |
US20030195175A1 (en) * | 2002-03-25 | 2003-10-16 | Deluca Hector F. | Use of carbon-2-modified-vitamin D analogs to induce the formation of new bone |
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Also Published As
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JPH03505330A (en) | 1991-11-21 |
JPH0667899B2 (en) | 1994-08-31 |
ZA907119B (en) | 1991-10-30 |
HU215604B (en) | 1999-01-28 |
AR246254A1 (en) | 1994-07-29 |
NO904854L (en) | 1990-11-08 |
CA1333616C (en) | 1994-12-20 |
US5237110A (en) | 1993-08-17 |
US5633241A (en) | 1997-05-27 |
RU2012558C1 (en) | 1994-05-15 |
WO1990010620A1 (en) | 1990-09-20 |
BR9004521A (en) | 1992-03-17 |
HU222491B1 (en) | 2003-07-28 |
AU5198890A (en) | 1990-10-09 |
RU2055068C1 (en) | 1996-02-27 |
HUT56538A (en) | 1991-09-30 |
US5710294A (en) | 1998-01-20 |
IL93455A0 (en) | 1990-11-29 |
NO904854D0 (en) | 1990-11-08 |
AU632315B2 (en) | 1992-12-24 |
KR950013636B1 (en) | 1995-11-13 |
US5880113A (en) | 1999-03-09 |
HU9802116D0 (en) | 1998-11-30 |
FI905489A0 (en) | 1990-11-06 |
HU902307D0 (en) | 1991-07-29 |
RO109331B1 (en) | 1995-01-30 |
US5618805A (en) | 1997-04-08 |
KR920700200A (en) | 1992-02-19 |
US5561123A (en) | 1996-10-01 |
IL93455A (en) | 1994-12-29 |
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